Publications by authors named "Kung-Hao Liang"

66 Publications

Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis.

Sci Rep 2021 12 2;11(1):23282. Epub 2021 Dec 2.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.

Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P < 0.001). A gene-signature score was derived from the deep transcriptome, capable of indicating patients' subsequent tumor recurrence (Hazard Ratio [HR] 1.645, confidence interval [CI] 1.337-2.025, P < 0.001) and mortality (HR 2.720, CI 1.798-4.112, P < 0.001). After the adjustment of baseline clinical factors, the score remains indicative of recurrence-free survival (HR 1.604, CI 1.292-1.992, P < 0.001) and overall survival (HR 2.781, CI 1.762-4.390, P < 0.001). Patients stratified by this score manifest not only distinct prognosis but also different molecular characteristics: Notch signaling ligands and receptors are comparatively overexpressed in patients with poorer prognosis, while tumor infiltrating natural killer cells are more abundant in patients with better prognosis. Additionally, immunohistochemical staining showed the DLL1 protein, a major ligand in the Notch signaling pathway, and the NCAM1 protein, a representative biomarker of natural killer cells, are present in the surgical tissues of patients of four molecular subgroups, WNT, SHH, Group 3 and Group 4. NCAM1 RNA level is also positively associated with the mutation burden in tumor (P = 0.023). The gene-signature score is validated successfully in the Canadian cohort (P = 0.009) as well as its three molecular subgroups (SHH, Group 3 and Group 4; P = 0.047, 0.018 and 0.040 respectively). In conclusion, pediatric medullablastoma patients can be stratified by gene-signature scores with distinct prognosis and molecular characteristics. Ligands and receptors of the Notch signaling pathway are overexpressed in the patient stratum with poorer prognosis. Tumor infiltrating natural killer cells are more abundant in the patient stratum with better prognosis.
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http://dx.doi.org/10.1038/s41598-021-02651-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639846PMC
December 2021

Tenofovir Hampers the Efficacy of Sorafenib in Prolonging Overall Survival in Hepatocellular Carcinoma.

Biomedicines 2021 Oct 26;9(11). Epub 2021 Oct 26.

Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.

Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The () gene can serve as a biomarker to guide HCC treatments. However, the enzyme substrates of its gene product, GalNAc-T14 (a glycosyltransferase), remained uncharacterized. Here, we conducted a glycoproteome-wide search for GalNAc-T14 substrates using lectin affinity chromatography followed by tandem mass spectrometry. Seventeen novel GalNAc-T14 substrates were identified. A connective map analysis showed that an antiviral drug, tenofovir, was the leading medicinal compound to down-regulate the expression of these substrates. In vitro assays showed that HCC cells were resistant to sorafenib if pretreated by tenofovir but not entecavir. Clinical analysis showed that the concomitant use of tenofovir and sorafenib was a previously unrecognized predictive factor for unfavorable overall survival (hazard ratio = 2.060, 95% confidence interval = [1.256, 3.381], = 0.004) in a cohort of 181 hepatitis-B-related, sorafenib-treated HCC patients (concomitant tenofovir versus entecavir treatment; = 0.003). In conclusion, by conducting a glycoproteome-wide search for GalNAc-T14 substrates, we unexpectedly found that tenofovir was a major negative regulator of GalNAc-T14 substrates and an unfavorable anti-hepatitis B drug in HCC patients receiving sorafenib.
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http://dx.doi.org/10.3390/biomedicines9111539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614833PMC
October 2021

The Aldehyde Dehydrogenase ALDH2*2 Allele, Associated with Alcohol Drinking Behavior, Dates Back to Prehistoric Times.

Biomolecules 2021 09 17;11(9). Epub 2021 Sep 17.

Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan.

Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and 126 residents who did not drink in their daily lives (AUDIT score = 0), using high-density single nucleotide polymorphism (SNP) arrays. The rs671 G > A manifests the highest significance of the association with drinking behavior (Fisher's exact P = 8.75 × 10). It is a pleiotropic, non-synonymous variant in the aldehyde dehydrogenase 2 (ALDH2) gene. The minor allele "A", commonly known as ALDH2*2, is associated with non-drinkers. Intriguingly, identity-by-descent haplotypes encompassing genomic regions with a median length of 1.6 (0.6-2.0) million nucleotide bases were found in all study participants with either heterozygous or homozygous ALDH2*2 ( = 81 and 13, respectively). We also analyzed a public-domain dataset with genome-wide genotypes of 2000 participants in Guangzhou, a coastal city in Southern China. Among them, 175 participants have homozygous ALDH2*2 genotype, and again, long ALDH2*2-carrying haplotypes were found in all 175 participants without exceptions. The median length of the ALDH2*2-carrying haplotype is 1.7 (0.5-2.8) million nucleotide bases. The haplotype lengths in the Keelung and Guangzhou cohorts combined indicate that the origin of the ALDH2*2 allele dates back to 7935 (7014-9381) years ago. In conclusion, the rs671 G > A is the leading genomic variant associated with the long-term drinking behavior among residents of Keelung, Taiwan. The ALDH2*2 allele has been in Asian populations since prehistoric times.
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http://dx.doi.org/10.3390/biom11091376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465343PMC
September 2021

Recent progress of biomarkers in oral cancers.

J Chin Med Assoc 2021 11;84(11):987-992

Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Oral cancers are the seventh most common cancer globally. While progresses in oral cancer treatment have been made, not all patients respond to these therapies in the same way. To overcome this difficulty, numerous studies have been devoted to identifying biomarkers, which enable early identification of patients who may benefit from a particular treatment modality or at risk for poor prognosis. Biomarkers are protein molecules, gene expression, DNA variants, or metabolites that are derived from tumors, adjacent normal tissue or bodily fluids, which can be acquired before treatment and during follow-up, thus extending their use to the evaluation of cancer progression and prediction of treatment outcome. In this review, we employed a basic significance level (<0.05) as the minimal requirement for candidate biomarkers. Effect sizes of the biomarkers in terms of odds ratio, hazard ratio, and area under the receiver operating characteristic curves were subsequently used to evaluate the potential of their clinical use. We identified the CCND1 from the tumor, human papillomavirus, HSP70, and IL-17 from the peripheral blood, and high density of CD45RO+ tumor-infiltrating lymphocytes as the clinically relevant biomarkers for oral cancers.
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http://dx.doi.org/10.1097/JCMA.0000000000000616DOI Listing
November 2021

Deep proteogenomic investigations elucidate the NRF2 antioxidant mechanism as a major driving mechanism of lung adenocarcinoma in Asia.

J Chin Med Assoc 2021 08;84(8):766-771

Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.

Background: Lung adenocarcinoma is a global leading cause of death. Despite modern therapeutic interventions, undesirable outcomes such as drug resistances and disease recurrence still occur. Therefore, continued investigations of disease driving mechanisms and counteracting strategies are urgently needed.

Methods: We re-visited two deep-proteogenomic resources of lung adenocarcinoma published recently. These resources were derived from patient cohorts with decent sizes in Taiwan and China. The gene set enrichment analysis (GSEA) was performed. A heatmap was produced by the generalized association plot (GAP).

Results: Among 189 common oncogenic pathways investigated, the nuclear factor erythroid 2-related factor 2 (NRF2) downstream antioxidant mechanism was uncovered for the first time the leading oncogenic mechanism of lung adenocarcinoma in Taiwan. The gene levels of NRF2 (also known as NFE2L2) is negatively correlated with those of KEAP1 (Pearson's correlation = -0.275, p = 0.009) in patients' tumor tissues. Furthermore, the protein levels of EIF2S2 and PGD are higher in patients with more advanced stages in the Taiwan cohort (p = 0.001 and 0.05, respectively), and are indicative of poorer progression-free survival (PFS) and overall survival (OS) in the China cohort (all Cox-regression p < 0.05). On the other hand, EPHX1 is higher in patients with earlier stages in Taiwan (p = 0.003), and are indicative of better PFS and OS in China (both Cox-regression p < 0.05). When the patients were stratified using the median protein abundances for Kaplan-Meier visualizations, patient strata with higher EIF2S2, PGD, and EPHX1 have significantly poorer PFS (log-rank p = 0.041); poorer OS (p = 0.006), and better PFS and OS (p = 0.001 and 0.030), respectively.

Conclusion: The NRF2 downstream antioxidant mechanism is one major driving mechanism of lung adenocarcinoma in Asia, and represents important directions for future therapeutic interventions. Major downstream proteins such as EIF2S2, PGD, and EPHX1 are indicative of cancer stages and prognosis.
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http://dx.doi.org/10.1097/JCMA.0000000000000577DOI Listing
August 2021

Plasma interleukin-17 and alpha-fetoprotein combination effectively predicts imminent hepatocellular carcinoma occurrence in liver cirrhotic patients.

BMC Gastroenterol 2021 Apr 17;21(1):177. Epub 2021 Apr 17.

Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.

Background: Predicting imminent hepatocellular carcinoma (HCC) in liver cirrhotic patients is an unmet medical need. We aimed to investigate circulatory biomarkers and their optimum combinations in a prospective study.

Methods: We investigated plasma interleukin 17 (IL-17) concentrations, quantified using enzyme-linked immunosorbent assay (ELISA), for the prediction of HCC in a large cohort of 404 HCC-naïve liver cirrhotic patients regularly followed after recruitment. Additionally, IL-17 in surgically resected tumor tissues were evaluated using immunohistochemistry staining.

Results: IL-17 was detected in HCC tissues. The IL-17 concentrations in the peripheral blood do not have correlation with an extensive list of 31 common demographic, metabolic and liver function variables in the cohort of liver cirrhotic patients. Furthermore, patients stratified by IL-17 and alpha-fetoprotein (AFP) showed distinctive cumulative incidence of HCC. Imminent HCC, defined here as HCC occurrence within 1 year, can be predicted by IL-17 alone with an area under the receiver operating characteristic curve [AUC] of 0.762 (P = 0.002). An multivariate analysis showed that age, hepatitis C viral infection, AFP and IL-17 were four independent factors associated with imminent HCC (adjusted P = 0.03, 0.041, 0.024 and 0.008 respectively). An explicit risk score (R) combining the concentrations of two plasma biomarkers, AFP and IL-17, achieved a high AUC of 0.933 (95% confidence interval 0.893-0.972, P < 0.001) in predicting imminent HCC, with 100% sensitivity and 79.9% specificity at the optimum cutoff. The score is defined as: [Formula: see text] CONCLUSIONS: The circulatory IL-17 concentration is a predictor of subsequent HCC occurrence in liver cirrhotic patients. The combination of AFP and IL-17 is highly effective in predicting imminent HCC within 1 year.
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http://dx.doi.org/10.1186/s12876-021-01761-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052794PMC
April 2021

Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development.

Hepatology 2021 08 26;74(2):641-655. Epub 2021 May 26.

Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background And Aims: PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion-defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo.

Approach And Results: Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case-control follow-up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072-9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133-6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real-time ATP assay, and calcium staining of preS2ΔMT-expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100-fold lower in preS2ΔMT-infected humanized Fah-/-/ Rag2-/-/Il2rg-/- triple knockout mice than in wild-type HBV-infected mice. PreS2ΔMT-infected mice displayed up-regulation of UPR and caspase-3 and enhanced liver fibrosis.

Conclusions: PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.
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http://dx.doi.org/10.1002/hep.31789DOI Listing
August 2021

Hepatitis B Virus Covalently Closed Circular DNA Predicts Postoperative Liver Cancer Metastasis Independent of Virological Suppression.

Cancers (Basel) 2021 Jan 31;13(3). Epub 2021 Jan 31.

Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.

New antiviral therapies against hepatitis B virus (HBV) focus on the elimination of covalently closed circular DNA (cccDNA). However, traditional cccDNA-specific quantitative PCR (qPCR) has a narrow effective range, hindering a reliable comparison between the levels of biopsy-derived cccDNAs. Collaterally, the prognostic role of cccDNA in HBV-related hepatocellular carcinoma (HCC) cannot be clearly defined. Here, we developed a peptide nucleic acid (PNA)-clamping qPCR method to provide a wider range of specific cccDNA quantification (up to 5 logs of effective range). Extrachromosomal DNA was extracted from para-neoplastic tissues for cccDNA quantification. In total, 350 HBV-related HCC patients were included for an outcome analysis. Without differential pre-dilution, cccDNA levels in para-neoplastic liver tissues were determined, ranging from < 2 × 10 to 123.0 × 10 copies/gram. The multivariate linear regression analysis showed that cccDNA was independently correlated with the HBV e antigen ( < 0.001) and serum HBV-DNA levels ( = 0.012). The Cox proportional hazard model analysis showed that cccDNA independently predicted overall survival ( = 0.003) and extrahepatic metastasis-free survival ( = 0.001). In virologically suppressed HCC patients, cccDNA still effectively predicted intrahepatic recurrence-free ( = 0.003) and extrahepatic metastasis-free ( = 0.009) survivals. In conclusion, cccDNA independently predicted postoperative extrahepatic metastasis-free survival.
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http://dx.doi.org/10.3390/cancers13030538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867012PMC
January 2021

Whole-Exome Sequencing Identified Novel Mutations in a Family With Congenital Short Bowel Syndrome Presenting Differently in Two Probands.

Front Genet 2020 15;11:574943. Epub 2020 Dec 15.

Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Children's Medical Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.

Congenital short bowel syndrome (CSBS) is a rare condition characterized by an inborn shortening of bowel length with loss of intestinal functions, which often combines malrotation. CXADR-like membrane protein () and filamin A () gene mutations are the two major causes of this inherited defect. We presented two siblings with the older brother suffering from a laparotomy for bowel obstruction due to malrotation on the 17th day after birth. The younger sister encountered a laparotomy for lactobezoar at 6 months old. CSBS was diagnosed by measurement of the bowel length during the operations. Compound heterozygous mutations with the paternal allele harboring a long deletion across exon 3-5 and the maternal allele bearing a non-sense mutation of exon 3 (c.235C > T, p.Q79) were identified in both cases. They are the first reported familial CSBS caused by novel mutations in Taiwan.
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http://dx.doi.org/10.3389/fgene.2020.574943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770137PMC
December 2020

Investigating seafood substitution problems and consequences in Taiwan using molecular barcoding and deep microbiome profiling.

Sci Rep 2020 12 15;10(1):21997. Epub 2020 Dec 15.

Institute of Food Safety and Health Risk Assessment, National Yang-Ming University, No. 155, Section 2, Linong St, Beitou District, Taipei City, 112, Taiwan.

Seafood is commonly seen in cuisines of the Asia-Pacific regions. The rates and consequences of seafood substitution frauds in Taiwan were elusive. To address this, we conducted a consumer-centered study, collecting seafood dishes and cooking materials from restaurants and markets easily accessible to the residents in Taiwan. Seafood substitutions were evaluated using DNA barcodes in the mitochondrial MT-CO1 gene. Among the 127 samples collected, 24 samples were mislabeled (18.9%, 95% Confidence interval [CI] = [12.5-26.8%]). The mislabel rates vary in different fish and product types (snapper [84.6%, 54.6-98.1%], cod [25%, 5.5-57.2%], swordfish [16.7%, 2.1-48.4%], cobia [16.7%, 0.4-64.1%], surimi products [100.0%]). A deep microbiome profiling was performed in 8 correctly-labeled conventional sushi and 2 tilapia sashimi mislabeled as snapper, with sequencing depths greater than 100,000 reads for every sample. The relative abundance of Pseudomonas genus is significantly higher in tilapia sashimi than in conventional sushi (P = 0.044). In conclusion, the gross seafood mislabel rate in Taiwan is 18.9% (12.5-26.8%). Snapper, cod and surimi products are particularly vulnerable to fraudulent substitutions. The high abundance of Pseudomonas in tilapia sashimi mislabeled as snapper unveils a potential health issue pertaining to the consumption of raw mislabeled seafood.
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http://dx.doi.org/10.1038/s41598-020-79070-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738519PMC
December 2020

Hepatitis B Virus preS/S Truncation Mutant rtM204I/sW196* Increases Carcinogenesis through Deregulated and .

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan.

Inevitable long-term therapy with nucleos(t)ide analogs in patients with chronic hepatitis B virus (HBV) infection has selected reverse-transcriptase (rt) mutants in a substantial proportion of patients. Some of these mutants introduce premature stop codons in the overlapping surface (s) gene, including rtA181T/sW172*, which has been shown to enhance oncogenicity. The oncogenicity of another drug-resistant mutant, rtM204I/sW196*, has not been studied. We constructed plasmids harboring rtM204I/sW196* and assessed the in vitro cell transformation, endoplasmic reticulum (ER) stress response, and xenograft tumorigenesis of the transformants. Cellular gene expression was analyzed by cDNA microarray and was validated. The rtM204I/sW196* transformants, compared with the control or wild type, showed enhanced transactivation activities for , increased cell proliferation, decreased apoptosis, more anchorage-independent growth, and enhanced tumor growth in mouse xenografts. X box-binding protein-1 () splicing analysis showed no ER stress response. Altered gene expressions, including up-regulated and , and downregulated transforming growth factor beta-induced (), were unveiled by cDNA microarray and validated by RT-qPCR. The alteration occurred in transformants with wild type or mutated HBV. The altered and were found only with mutated HBV. The rtM204I/sW196* preS/S truncation may endorse the cell transformation and tumorigenesis ability via altered host gene expressions, including and . Downregulated may be a common mechanism for oncogenicity in HBV surface truncation mutants.
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http://dx.doi.org/10.3390/ijms21176366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503731PMC
September 2020

Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression.

Hepatol Int 2020 Dec 7;14(6):973-984. Epub 2020 Aug 7.

Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.

Background: Hepatitis B virus (HBV) X gene (HBx) mutants can develop during the natural course of chronic HBV infection. However, little is known about whether the emergence of HBx mutants during long-term antiviral therapy is an adaptation of HBV to antiviral stress. This study was to identify HBx mutants that emerged in patients experiencing Lamivudine resistance or suboptimal treatment.

Methods: Forty-six Lamivudine-resistant patients and 46 patients with suboptimal treatment responses to Entecavir were enrolled in this study. HBx mutants were identified by sequence analysis and their roles in the HBV replication cycle were characterized.

Results: We show that deletion/truncation/insertion mutations were only detected in the Lamivudine resistance group, while synonymous mutations were found in both groups. Follow-up analyses revealed that five patients in the Lamivudine group developed hepatocellular carcinoma, while patients in the Entecavir group did not. These mutants were characterized by a significant decrease in transactivation of the pre-S1 promoter, and varying effects on transactivation of the X promoter. Co-transfection of HBx-mutant plasmid and HBV replication-competent clone into HepG2 cells resulted in increased nuclear-to-cytoplamic HBV core antigen, HBV-DNA ratios, and nuclear covalently closed circular DNA (cccDNA). Antiviral drug sensitivity assays revealed that these mutants exhibited a compensatory effect to counteract antiviral drug suppression, resulting in elevated secretory HBV-DNA levels.

Conclusions: Our study demonstrates that HBx mutants can emerge during Lamivudine or Entecavir therapy. These mutants exhibit altered transactivation of the HBV pre-S1 and X promoters, leading to increased cccDNA levels to compensate for replication suppression.
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http://dx.doi.org/10.1007/s12072-020-10079-1DOI Listing
December 2020

Plasma phenylalanine and glutamine concentrations correlate with subsequent hepatocellular carcinoma occurrence in liver cirrhosis patients: an exploratory study.

Sci Rep 2020 07 2;10(1):10926. Epub 2020 Jul 2.

Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.

Aberrant metabolisms have been hypothesized to precede the occurrence of hepatocellular carcinoma (HCC), therefore, we investigated biomarkers associated with subsequent HCC in peripheral bloods using metabolomic technologies. A cohort of 475 HCC-naïve liver cirrhotic patients were recruited and prospectively followed. A total of 39 patients developed HCC in the follow-up period. Baseline plasma metabolites were explored using untargeted nuclear magnetic resonance. Candidates were then quantified by ultra-performance liquid chromatography. A series of univairiate and multivariate analysis showed that Phenylalanine (Phe) and Glutamine (Gln) levels are associated with time to HCC, independent of viological etiologies and age. A HCC risk score R was then constructed using the polynomial combination of age, Phe and Gln in the units of micromolar (μM):[Formula: see text] R correlates with the time to HCC significantly (Hazard ratio [HR] = 2.368, 95% confidence interval [CI] 1.760-3.187, P < 0.001). An additional cross-sectional analysis showed that Phe and Gln concentrations both correlates with HCC occurrence in the next 3 years (area under the receiver operating characteristic curve [AUC] = 0.607 and 0.629, P = 0.033 and 0.010 respectively). In conclusion, phenylalanine and glutamine concentrations in the peripheral blood correlate with subsequent HCC.
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http://dx.doi.org/10.1038/s41598-020-67971-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331577PMC
July 2020

Hunting severe acute respiratory syndrome coronavirus 2 (2019 novel coronavirus): From laboratory testing back to basic research.

J Chin Med Assoc 2020 06;83(6):524-526

Institute of Food Safety and Health Risk Assessment, National Yang-Ming University, Taipei, Taiwan, ROC.

The rapid spread of coronavirus disease 2019 (COVID-19) in many countries causes citizens of daily inconvenience and even life-threat for elderly population. The invasion of the main pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; 2019 novel coronavirus [2019-nCoV]), into human body causes different levels of impact to various patients. One of the most important issues for COVID-19 is how to defend this virus with the ability to foresee the infected targets. Thus, we maintain the quarantined essentially as for as others saved from COVID-19. So far, the routine laboratory test to confirm whether infected by SARS-CoV-2/2019-nCoV or not is through real-time reverse transcription polymerase chain reaction (rRT-PCR; quantitative polymerase chain reaction [qPCR]) with certain sequence regions that recognize SARS-CoV-2/2019-nCoV RNA genome. The heavy loading of rRT-PCR (qPCR) machine and handling labor have tight-packed the instruments as well as the manpower almost in every country. Therefore, the alternative approaches are eagerly waiting to be developed. In this review article, we sort out some state-of-the-art novel approaches that might be applied for a fast, sensitive, and precise detection of SARS-CoV-2/2019-nCoV not only to help the routine laboratory testing but also to improve effective quarantine.
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http://dx.doi.org/10.1097/JCMA.0000000000000332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199774PMC
June 2020

Novel biosensor platforms for the detection of coronavirus infection and severe acute respiratory syndrome coronavirus 2.

J Chin Med Assoc 2020 08;83(8):701-703

Microscopy Service Laboratory, Basic Research Division, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

The recent outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been causing respiratory diseases globally, damaging wide ranges of social-economic activities. This virus is transmitted through personal contact and possibly also through ambient air. Effective biosensor platforms for the detection of this virus and the related host response are in urgent demand. These platforms can facilitate routine diagnostic assays in certified clinical laboratories. They can also be integrated into point-of-care products. Furthermore, environmental biosensors can be designed to detect SARS-CoV-2 in the ambient air or in the intensive care ventilators. Here, we evaluate technical components of biosensors, including the biological targets of recognition, the recognition methods, and the signal amplification and transduction systems. Effective SARS-CoV-2 detectors can be designed by an adequate combination of these technologies.
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http://dx.doi.org/10.1097/JCMA.0000000000000337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493778PMC
August 2020

The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago.

J Hum Genet 2020 Jul 3;65(7):619-625. Epub 2020 Apr 3.

Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.
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http://dx.doi.org/10.1038/s10038-020-0745-7DOI Listing
July 2020

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan.

Cancers (Basel) 2020 Mar 11;12(3). Epub 2020 Mar 11.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.
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http://dx.doi.org/10.3390/cancers12030653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139704PMC
March 2020

Ages of hepatocellular carcinoma occurrence and life expectancy are associated with a UGT2B28 genomic variation.

BMC Cancer 2019 Dec 5;19(1):1190. Epub 2019 Dec 5.

Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: Hepatocellular carcinoma (HCC) is an aggressive solid tumor. HCC occurred at younger and elder ages were considered driven by different oncogenic mechanisms, and they demonstrated distinct clinical courses.

Methods: A total of 382 HCC patients treated by surgical resections was analyzed.

Results: A univariate-multivariate analysis showed that viral etiology (chronic hepatitis B, C) and the UDP glucuronosyltransferase family 2 member B28 (UGT2B28) genomic variant rs2132039 were independently associated with the age at presentation of HCC (all adjusted P < 0.05). An extensive evaluations of clinicalpathological factors showed that the age (Odds ratio [OR], 1.016; 95% confidence interval [CI], 1.001-1.032; adjusted P = 0.037) and ascites (OR, 3.505; CI, 1.358-9.048; adjusted P = 0.010) were two independent factors associated with this genomic variant. The age was 54.1 ± 14.6 years for patients with the "TT" variant type, and 58.2 ± 13.7 years for those with the "Non-TT" variant type. The age disparity was most prominent in alcoholic patients (OR, 1.079; CI, 1.035-1.125; P < 0.001, age of "TT", 49.6 ± 12.2; age of "non-TT", 59.3 ± 10.7). This genomic variant was also associated with age of recurrence (P = 0.025), distant metastasis (P = 0.024) and HCC-related death (P = 0.008) in non-censored patients.

Conclusions: An UGT2B28 genomic variant was indicative of the age of HCC presentation, recurrence, distant metastasis and death.
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http://dx.doi.org/10.1186/s12885-019-6409-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896495PMC
December 2019

Morphomic Signatures Derived from Computed Tomography Predict Hepatocellular Carcinoma Occurrence in Cirrhotic Patients.

Dig Dis Sci 2020 07 2;65(7):2130-2139. Epub 2019 Nov 2.

Morphomic Analysis Group, University of Michigan Medical School, Ann Arbor, MI, USA.

Background And Aims: Computed tomography (CT) provides scans of the human body from which digitized features can be extracted. The aim of this study was to examine the role of these digital biomarkers for predicting subsequent occurrence of hepatocellular carcinoma (HCC) in cirrhotic patients.

Methods: A cohort of 269 patients with cirrhosis were recruited and prospectively followed for the occurrence of HCC in Taiwan. CT scans were retrospectively retrieved and computationally processed using analytic morphomics. A predictive score was constructed using Cox regression and the generalized iterative modeling method, maximizing the log likelihood of the time to HCC development. An independent cohort of 274 patients from University of Michigan was utilized to examine the predictive validity of this score in a Western population.

Results: Of the 27 digitized features at the 12th thoracic vertebral level, six features were significantly associated with HCC occurrence. Two digitized features (fascia eccentricity and the bone mineral density) were able to stratify patients into high- and low-risk groups with distinct cumulative incidence of HCC in both the training and validation cohorts (P = 0.015 and 0.044, respectively). When the two digitized features were tested in the Michigan cohort, only bone mineral density remained an effective predictor.

Conclusion: Digitized features derived from the CT were effective in predicting subsequent occurrence of HCC in cirrhosis patients. The bone mineral density measured on CT was an effective predictor for patients in both Taiwan and USA.
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http://dx.doi.org/10.1007/s10620-019-05915-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195221PMC
July 2020

A GALNT14 rs9679162 genotype-guided therapeutic strategy for advanced hepatocellular carcinoma: systemic or hepatic arterial infusion chemotherapy.

Pharmacogenomics J 2020 02 14;20(1):57-68. Epub 2019 Oct 14.

Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Although targeted agents are recommended as the first-line treatments for advanced hepatocellular carcinoma (aHCC), systemic chemotherapy or hepatic arterial infusion chemotherapy (HAIC) are still being used in Asian countries. Beside economic considerations, it was found that targeted drugs could not significantly prolong overall survival in aHCC patients with distant metastasis. In addition, chemotherapy could achieve complete response in a small proportion of patients. Here, we aimed to investigate whether combination of three previously identified single nucleotide polymorphism (SNP) predictors (GALNT14-rs9679162, WWOX-rs13338697, and rs6025211) could guide our choice between systemic chemotherapy, HAIC, and targeted agents in aHCC patients. A cohort of 237 real-world aHCC patients (171 receiving systemic chemotherapy followed by various anticancer treatments including sorafenib; 66 receiving HAIC) were included for outcome analysis. By combining the three SNP markers with or without addition of two clinical criteria (tumor diameter <8 cm, neutrophils <80%), small groups of patients were found to harbor high complete response rates to systemic chemotherapy (35.3% if the 3-SNP signature alone matched; 60.0% if clinical criteria also matched). Subsequent sorafenib treatment for chemotherapy non-responders was associated with longer overall survival (P < 0.001). In HAIC-treated patients, GALNT14-rs9679162 genotype "GG" was associated with longer overall survival (P = 0.019, median survival > 10.5 months). In conclusion, pre-test for the 3-SNP signature in aHCC patients could identify potential systemic chemotherapy or HAIC responders. Chemotherapy non-responders still benefited from subsequent sorafenib treatment. Accordingly, we propose a roadmap for aHCC patients when chemotherapy or HAIC is to be used.
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http://dx.doi.org/10.1038/s41397-019-0106-0DOI Listing
February 2020

The methionine salvage pathway-involving ADI1 inhibits hepatoma growth by epigenetically altering genes expression via elevating S-adenosylmethionine.

Cell Death Dis 2019 03 11;10(3):240. Epub 2019 Mar 11.

Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

The 5'-methylthioadenosine (MTA) cycle-participating human acireductone dioxygenase 1 (ADI1) has been implicated as a tumor suppressor in prostate cancer, yet its role remains unclear in hepatocellular carcinoma (HCC). Here, we demonstrated a significant reduction of ADI1, either in protein or mRNA level, in HCC tissues. Additionally, higher ADI1 levels were associated with favorable postoperative recurrence-free survival in HCC patients. By altering ADI1 expression in HCC cells, a negative correlation between ADI1 and cell proliferation was observed. Cell-based and xenograft experiments were performed by using cells overexpressing ADI1 mutants carrying mutations at the metal-binding sites (E94A and H133A, respectively), which selectively disrupted differential catalytic steps, resulting in staying or leaving the MTA cycle. The results showed that the growth suppression effect was mediated by accelerating the MTA cycle. A cDNA microarray analysis followed by verification experiments identified that caveolin-1 (CAV1), a growth-promoting protein in HCC, was markedly decreased upon ADI1 overexpression. Suppression of CAV1 expression was mediated by an increase of S-adenosylmethionine (SAMe) level. The methylation status of CAV1 promoter was significantly altered upon ADI1 overexpression. Finally, a genome-wide methylation analysis revealed that ADI1 overexpression altered promoter methylation profiles in a set of cancer-related genes, including CAV1 and genes encoding antisense non-coding RNAs, long non-coding RNAs, and microRNAs, resulting in significant changes of their expression levels. In conclusion, ADI1 expression promoted MTA cycle to increase SAMe levels, which altered genome-wide promoter methylation profiles, resulting in altered gene expression and HCC growth suppression.
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http://dx.doi.org/10.1038/s41419-019-1486-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411897PMC
March 2019

Multiple doses of hepatitis B recombinant vaccine for chronic hepatitis B patients with low surface antigen levels: a pilot study.

Hepatol Int 2018 Sep 7;12(5):456-464. Epub 2018 Aug 7.

Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.

Background: Seroclearance of hepatitis B surface antigen (HBsAg) has been rarely achieved in the treatment of chronic hepatitis B (CHB) patients. We administered HBsAg-based recombinant vaccine in patients with low HBsAg concentrations.

Methods: Twenty hepatitis B e antigen-negative patients, with HBsAg < 1000 IU/ml, were enrolled. Vaccines were administered every 8 weeks for 48 weeks (seven doses). HBsAg levels and anti-HBs were assayed longitudinally until 48 weeks post-vaccination. HLA genotyping and cDNA microarray were performed to search for response predictors.

Results: Nineteen patients completed the study. At the end of vaccination, HBsAg declined significantly (Δ = - 0.27 ± 0.49 log IU/ml, p = 0.0005). The annual decline rate was significantly greater than that of an age-, gender-, and baseline HBsAg-matched control group (Δ = - 0.18 ± 0.46 versus + 0.11 ± 0.42 log IU/ml/year; p = 0.0229). Two patients achieved HBsAg seroclearance. Fourteen had significant HBsAg decline (Δ = - 0.64 ± 0.88 log IU/ml). No significant adverse events occurred during the trial. cDNA microarray identified the top up- and down-regulated genes in responders as HLA-DQ and HLA-DMB, respectively. HLA genotyping identified HLA-DQB1*04, HLA-DRB1*04, and HLA-B*40 as predictors for non-response (p = 0.0499, 0.0152, and 0.0314, respectively).

Conclusions: In low-level HBsAg CHB patients, serial HBsAg-based vaccinations were safe, resulting in significant HBsAg decline. HLA gene expression and genotypes played a role in vaccine responsiveness (ClinicalTrials.gov Identifier: NCT01817725).
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http://dx.doi.org/10.1007/s12072-018-9890-xDOI Listing
September 2018

A novel risk score for hepatocellular carcinoma in Asian cirrhotic patients: a multicentre prospective cohort study.

Sci Rep 2018 06 5;8(1):8608. Epub 2018 Jun 5.

Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.

Liver cirrhotic patients suffer from a seemingly unpredictable risk of hepatocellular carcinoma (HCC). Here, an HCC risk score R (0 ≦ R ≦ 1) was derived from commonly tested haematological and biochemical parameters. In the score-derivation Taiwanese cohort (144 cirrhosis versus 48 HCC-remission patients), the score had an area-under-the-curve (AUC) of 0.70 (95% confidence interval [CI], 0.61-0.78, P < 0.001). When validated in a Korean cohort (78 cirrhosis versus 23 HCC-remission patients), the AUC was 0.68 (CI, 0.56-0.80, P = 0.009). In a multicentre prospective cohort (478 cirrhotic patients prospectively followed for HCC occurrence), the hazard ratio with respect to R was 2.344 (CI = 1.183-4.646, P = 0.015). The cumulative incidences of HCC at two years after patient enrolment were 9.6% and 1.7% for the high-risk (R ≧ 0.5) and low-risk (R < 0.5) groups, respectively (P < 0.001). At the end of the study, the incidences were 10.9% and 5.0%, respectively (P = 0.012). The majority of HCCs (23/26) in the high-risk group emerged within the first two years of follow-up. In conclusion, an HCC risk score was developed for cirrhotic patients that effectively predicted HCC in a prospective cohort study.
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http://dx.doi.org/10.1038/s41598-018-26992-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988718PMC
June 2018

Development of a fibrosis index including hepatitis B virus basal core promoter A1762T mutation for pretherapeutic evaluation.

J Gastroenterol Hepatol 2018 Aug 12;33(8):1530-1537. Epub 2018 Mar 12.

Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Background And Aim: Commonly used non-invasive fibrosis scores usually included serum transaminase levels in the equations, including Aspartate transaminase to Platelet Ratio Index (APRI) and fibrosis-4 (FIB-4). Transaminases fluctuated significantly in chronic hepatitis B patients with exacerbations, leading to unsteady score values. As such, here, we aim to develop a transaminase-free score suitable for pretherapeutic evaluation of fibrosis stages.

Methods: Firstly, 1082 treatment-naïve chronic hepatitis B patients were enrolled and divided into modeling (n = 541) and verification (n = 541) cohorts. Secondly, 265 patients having received liver biopsy, with known Ishak fibrosis stages, were included for independent correlation.

Results: Cross-sectional analysis of 1082 patients revealed age-dependent variation of association between virological factors and cirrhosis. A fibrosis score including Anti-hepatitis B e antibody, Basal core promoter (BCP) A1762T mutation, and Platelet count Index (named ABPI) was derived from the modeling cohort. ABPI performed better than APRI and FIB-4 in the verification cohort for identifying cirrhotic patients (comparison of area under the receiver operating characteristic curves: ABPI vs APRI and FIB-4 = 0.785 vs 0.563 [P < 0.001] and 0.700 [P = 0.026], respectively). The performance of ABPI was even better in young (< 40 years old) hepatitis B patients (area under the receiver operating characteristic curves: 0.856 vs 0.402 [P < 0.001] and 0.599 [P = 0.009], respectively). Finally, in the independent cohort of 265 patients with known Ishak fibrosis stages, it was found that ABPI effectively distinguished between Ishak fibrosis stages 3 and > 3 and between 4 and > 4 (P < 0.001 for each).

Conclusions: We developed a transaminase-free fibrosis score (ABPI) utilizing basal core promoter A1762T data, which outperformed APRI and FIB-4.
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http://dx.doi.org/10.1111/jgh.14120DOI Listing
August 2018

Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation.

Oncotarget 2017 Oct 18;8(47):82280-82293. Epub 2017 Jul 18.

Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.

Melatonin is the primary pineal hormone that relays light/dark cycle information to the circadian system. It was recently reported to exert intrinsic antitumor activity in various cancers. However, the regulatory mechanisms underlying the antitumor activity of melatonin are poorly understood. Moreover, a limited number of studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), a major life-threatening malignancy in both sexes in Taiwan. In this study, we investigated the antitumor effects of melatonin in HCC and explored the regulatory mechanisms underlying these effects. We observed that melatonin significantly inhibited the proliferation, migration, and invasion of HCC cells and significantly induced the expression of the transcription factor FOXA2 in HCC cells. This increase in FOXA2 expression resulted in upregulation of lncRNA-CPS1 intronic transcript 1 (CPS1-IT1), which reduced HIF-1α activity and consequently resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the experiments confirmed that melatonin exerts tumor suppressive effects by reducing tumor growth. In conclusion, our findings suggested that melatonin inhibited HCC progression by reducing lncRNA-CPS1-IT1-mediated EMT suppression and indicated that melatonin could be a promising treatment for HCC.
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http://dx.doi.org/10.18632/oncotarget.19316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669889PMC
October 2017

Combinations of single nucleotide polymorphisms WWOX-rs13338697, GALNT14-rs9679162 and rs6025211 effectively stratify outcomes of chemotherapy in advanced hepatocellular carcinoma.

Asia Pac J Clin Oncol 2018 Apr 11;14(2):e54-e63. Epub 2017 Jul 11.

Liver Research Center and Department of Hepato-Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Aim: A genome-wide association study (GWAS) had identified a single nucleotide polymorphism (SNP), GALNT14-rs9679162, capable of predicting chemotherapy responses in advanced hepatocellular carcinoma (HCC). Here, we revisited the GWAS database to search for necessary SNPs that could improve our outcome prediction.

Methods: A cohort of 116 HCC patients receiving split-dose chemotherapy composed of 5-fluorouracil, mitoxantrone and cisplatin was enrolled. The GALNT14-rs9679162 together with four other leading candidate SNPs (rs6025211, rs715171, LOC105369482-rs1955024 and WWOX-rs13338697) was genotyped and correlated with time-to-tumor progression (TTP) and overall survival (OS).

Results: GALNT14-rs9679162-TT genotype remained an effective predictor for favorable TTP and OS (P = 0.012 and 0.002). Additionally, it was found that WWOX-rs13338697-CT genotype was associated with unfavorable TTP (P = 0.031), independent of GALNT14-rs9679162 genotype (adjusted P = 0.045), and rs6025211-CT genotype was associated with unfavorable OS (P = 0.014), independent of GALNT14-rs9679162 genotype (adjusted P = 0.025). Combinations of these SNPs stratified patients into three groups with differential treatment outcomes. Patients with GALNT14-rs9679162-TT/WWOX-rs13338697-non-CT genotypes achieved the most favorable treatment outcomes (n = 19; median TTP, median OS and response rate were 3.9 months, 6.8 months and 4/19 [21.1%], respectively); whereas patients with GALNT14-rs9679162-non-TT/rs6025211-CT genotypes associated with the most unfavorable treatment outcomes (n = 40; median TTP, median OS and response rate were 1.9 months, 3.5 months and 1/40 [2.5%], respectively). The remaining patients constituted a third subgroup with intermediate clinical outcomes.

Conclusions: Three genetic variants, GALNT14-rs9679162, WWOX-rs13338697 and rs6025211, stratified advanced HCC patients into three groups with differential treatment outcomes.
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http://dx.doi.org/10.1111/ajco.12745DOI Listing
April 2018

Clinical Predictors for Neutrophil-to-Lymphocyte Ratio Changes in Patients with Chronic Hepatitis B Receiving Peginterferon Treatment.

In Vivo 2017 Jul-Aug;31(4):723-729

Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, R.O.C.

Background: A lower neutrophil-to-lymphocyte ratio (NLR) was found to be associated with better clinical outcomes in hepatitis B-related liver cirrhosis and hepatocellular carcinoma. We aimed to identify pre-therapeutic variables capable of predicting NLR changes in patients with hepatitis B receiving peginterferon therapy.

Patients And Methods: The baseline clinicopathological data were analyzed to correlate with NLR changes before and 1 year after peginterferon treatment in 71 patients with hepatitis B.

Results: Univariate analysis revealed that pre-treatment NLR itself negatively predicted NLR changes following peginterferon treatment (odds ratio(OR)=0.320, p=0.013). Further analysis identified pre-treatment NLR, hemoglobin and hepatitis B surface antigen level as independent predictors for NLR changes (adjusted p=0.028, 0.005, and 0.028, respectively). A predictive score composed of these three factors had an area under the curve of 76.5% (p<0.001).

Conclusion: Pretreatment NLR, hemoglobin and hepatitis B surface antigen level in combination, effectively predicted NLR changes following peginterferon treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566930PMC
http://dx.doi.org/10.21873/invivo.11121DOI Listing
March 2018

genotype is associated with perineural invasion, lymph node metastasis and overall survival in resected cholangiocarcinoma.

Oncol Lett 2017 Jun 5;13(6):4215-4223. Epub 2017 Apr 5.

Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, R.O.C.

Cholangiocarcinoma is a rare, sporadic and aggressive type of cancer. The genetic basis of cholangiocarcinoma remains poorly understood. The present study investigated the prognostic role of the N-acetylgalactosaminyltransferase 14 ()-rs9679162 genotype, an effective therapeutic response predictor for hepatocellular carcinoma in patients with cholangiocarcinoma receiving surgical resection. A cohort of patients with intrahepatic or perihilar cholangiocarcinoma (n=112) were retrospectively recruited. Of these patients, 31.3, 49.1 and 19.6% had 'TT', 'TG' and 'GG' genotypes, respectively. The patient's genotype distributions did not deviate significantly from those of the ethnic reference cohorts, HapMap-Chinese Han Beijing and Chinese Han Metropolitan Denver. The genotype 'TT' was associated with unfavorable overall survival in univariate analysis (P=0.023). Furthermore, two tumor characteristics, perineural and vascular invasion, were independently associated with unfavorable overall survival (P=0.001 and P=0.002, respectively). The 'TT' genotypes were independently associated with two known predictors of unfavorable prognosis, perineural invasion (P=0.035) and lymph node metastasis (P=0.005) in a multivariate linear regression analysis. When compared with the two reference genotype cohorts, the 'TT' genotype was significantly higher in patients with perineural invasion (P=0.049, Beijing cohort; P=0.034, Denver cohort). Similar enrichment of the 'TT' genotype was also revealed in patients with lymph node metastasis (P=0.046, Beijing cohort; P=0.032 Denver cohort). In conclusion, the G-rs9679162 'TT' genotype was associated with perineural invasion and lymph node metastasis, as well as unfavorable overall survival in patients with resected cholangiocarcinoma.
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http://dx.doi.org/10.3892/ol.2017.5991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452896PMC
June 2017

Intrahepatic HCV RNA Level and Genotype 1 Independently Associate with Hepatic Reticulon 3 Expression.

Anticancer Res 2017 06;37(6):2885-2891

Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, R.O.C.

Background /Aim: Reticulon 3 (RTN3), resides predominantly in the endoplasmic reticulum and has opposite regulatory effects on Hepatitis C virus (HCV) replication through interacting with NS5A and NS4B proteins. This study aimed to unravel the actual effect of RTN3 on HCV replication.

Materials And Methods: A total of 115 HCV-related hepatocellular carcinoma patients receiving hepatectomy was enrolled in this study. The hepatic HCV RNA and RTN3 protein levels in the non-cancerous liver tissues were examined for clinical analysis.

Results: Of the 115 patients, 16 (11.5%) were occult HBV infection (positive for tissue HBV DNA. Univariate followed by multivariate analysis revealed that intrahepatic RTN3 levels were independently associated with higher HCV viral load (p=0.018) and HCV genotype 1 (p=0.017). Multivariate analysis revealed that HCV genotype 1, tumor size, albumin and aspartate transaminase associated with a shorter recurrence-free survival (p<0.05).

Conclusion: Higher intrahepatic RTN3 levels independently correlated with higher intrahepatic HCV RNA levels and genotype 1 HCV.
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http://dx.doi.org/10.21873/anticanres.11641DOI Listing
June 2017

A Multivariate Evaluation of Factors Affecting the Quality of Freshly Frozen Tissue Specimens.

Biopreserv Biobank 2017 Aug 25;15(4):344-349. Epub 2017 May 25.

1 Tissue Bank, Chang Gung Memorial Hospital , Linko, Taiwan .

Well-prepared and preserved freshly frozen specimens are indispensable materials for clinical studies. To manage specimen quality and to understand the factors potentially affecting specimen quality during preservation processes, we analyzed the quality of RNA and genomic DNA of various tissues collected between 2002 and 2011 in Linkou Chang Gung Memorial Hospital, Taiwan. During this period, a total of 1059 freshly frozen specimens from eight major cancer categories were examined. It was found that preservation duration, organ origin, and tissue type could all influence the quality of RNA samples. The increased preservation period correlated with decreased RNA quality; the brain, breast, and stomach RNA specimens displayed faster degradation rates than those of other organs, and RNA specimens isolated from tumor tissues were apparently more stable than those of other tissues. These factors could all be used as quality predictors of RNA quality. In contrast, almost all analyses revealed that the genomic DNA samples had good quality, which was not influenced by the aforementioned factors. The results assisted us in determining preservation factors that affect specimen quality, which could provide evidence for improving processes of sample collection and preservation. Furthermore, the results are also useful for researchers to adopt as the evaluation criteria for choosing specimen collection and preservation strategies.
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http://dx.doi.org/10.1089/bio.2016.0104DOI Listing
August 2017
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